The primary goal of this project is to determine the role of variation in HIV sequences in causing the various clinical manifestations seen in AIDS. Variation in the polymerase gene associated with resistance to certain drug combinations have been studied by molecular cloning and in vitro analysis of drug resistance. The role of individual amino acid alterations has been determined by these studies. Variation in the envelope gene has been studied both in vivo and in vitro. In vivo env sequence analysis of viruses associated with dementia suggested that unique viral strains may be responsible for the occurrence of HIV dementia. In contrast, other analyses indicated that dementia was not associated with higher levels of viral DNA. The influence of the V3 region of the envelope gene on macrophage tropism and the NSI and SI phenotypes was mapped to individual V3 amino acids, and it was found that usually macrophage tropism and the SI phenotype were independently determined by amino acids at different V3 positions. This finding provides an explanation for the occurrence of HIV strains which exhibit both the SI phenotype and macrophage tropism.